Annual review of physiology最新文献

Polycyclic aromatic hydrocarbons (PAHs) are released into the environment primarily through industrial processes and the incomplete combustion of organic matter. Their persistence in air, water, and soil facilitates widespread environmental distribution and exposure that directly impact the health of humans, other animals, and ecosystems. In recent years, the 3-ringed PAH phenanthrene has drawn particular interest for its specific cardiotoxicity. Phenanthrene can be transformed in the environment and within the body, leading to metabolites that can also influence heart function. Overall, phenanthrene and its derivatives alter the electrical activity of the heart by inhibiting repolarizing (e.g., I _K) currents and inhibiting depolarizing (e.g., I _Na and I _Ca) currents, which increase the probability of arrhythmias. Phenanthrene and its derivatives also impact cardiac contractility by reducing the amplitude of the intracellular Ca2+ transient in all species examined to date. This review begins by describing the sources and sinks of environmental phenanthrene and how it enters and accumulates within organisms. It then focuses on the potential for, and mechanisms of, modulation of cardiac activity by phenanthrene and its derivatives at the molecular, cellular, intact heart, and whole organism levels. The results provide a comprehensive summary of the propensity of phenanthrene to modulate vertebrate cardiac function, from fish exposed via crude oil to humans breathing polluted air.

Life on earth evolved under daily cycles of sunlight, and all species developed mechanisms for detecting and responding to solar wavelengths reaching the surface of the earth. Early phototransduction studies found that our eyes detect visible wavelengths using light-activated G protein-coupled receptors named opsins. Many years after discovering the mechanisms by which of rhodopsin (opsin 2) and the cone opsins (opsin 1) mediate vision, three other members of the opsin family (opsins 3, 4, and 5) were identified and, surprisingly, found to be expressed in the brain and peripheral organs. Named nonvisual opsins (NVOs), these receptors mediate physiological light responses, such as pupillary light reflex and circadian rhythms. NVOs have been the focus of an increasing number of extraocular phototransduction studies, illuminating novel ways in which light modulates human physiology. This review summarizes our current knowledge on signaling mechanisms mediating nonvisual photoreception and their physiological functions.

Pain is a fundamental human experience, but how does it begin? Noxious stimuli elicit strong behavioral and physiological responses, even in the youngest newborns, reflecting early subcortical engagement, but the actual experience of pain requires higher cortical processes. This review summarizes current knowledge on how pain associated with tissue injury is represented in the newborn brain. It explores the nature of nociceptive input to the infant brain, the role of immature cortical networks in interpreting this input, and the influence of biological and external factors on these mechanisms. We outline current methods for recording infant brain activity during clinical tissue-damaging procedures, review collected data, and address common misconceptions in the field. We also discuss the differential maturation of sensory, emotional, and cognitive brain systems involved in pain, and propose a model of how the representation of pain evolves as the underlying neural networks develop.

Pulmonary fibrosis is a devastating and progressive disease marked by replacement of gas-exchanging tissue with collagen-rich scar. The mechanical environment is profoundly altered in pulmonary fibrosis and contributes to disease progression via feedback relationships between cells, the extracellular matrix, and the evolving mechanical environment. Targeting these mechanobiological feedback loops has emerged as a promising approach to interrupt disease progression, though with challenges in how to intervene selectively, safely, and effectively. We posit that further delineation of cell-matrix mechanobiological interactions will be pivotal to promoting fibrosis resolution and should guide efforts to discover and implement new approaches that can preserve or even restore lung function. To set the stage for these advances, we first review the mechanobiology of the healthy lung and the feedback loops that promote fibrosis progression. We then lay out the challenges and opportunities for targeting the fibrotic matrix as an essential element for protecting or restoring lung function.

Connexin hemichannels are pivotal for cellular communication, acting as independent conduits for ion and metabolite exchange, as well as precursors to gap junction channels. While their involvement in pathophysiological conditions, including cardiovascular, neurodegenerative, and inflammatory diseases, is well-documented, their physiological roles in tissue homeostasis and cellular signaling remain under active investigation. Despite considerable progress, our understanding of the mechanisms governing hemichannel gating, permeation, structural dynamics, and regulation remains incomplete. This review summarizes key foundational insights into recent advancements to offer a comprehensive perspective on hemichannel function. We explore the molecular determinants of hemichannel opening and closing, their interactions with cellular signaling networks, and structural adaptations that modulate permeation and gating. By integrating these findings, we highlight emerging concepts in connexin hemichannel regulation and underscore their potential as novel therapeutic targets in a variety of disease contexts.

Mitochondrial ATP production dynamically adapts to cellular energy demands, with calcium (Ca2+) playing a crucial regulatory role. In this review, we critically evaluate the evidence for intramitochondrial Ca2+ ([Ca2+]_m) sensitivity in key energy metabolic pathways, highlighting the [Ca2+]_m dependence of specific mitochondrial systems. We also address the metabolic consequences of [Ca2+]_m-sensitive ATP production, particularly its effects on the utilization of specific macronutrients that fuel ATP production. Next, we discuss the primary Ca2+ entry pathway into the matrix, the mitochondrial Ca2+ uniporter (MCU), its macromolecular complex structure (MCUcx), and allosteric regulation by Ca2+. Key to this regulation are specific auxiliary subunits, along with the influence of mitochondrial inner membrane architecture. While the Ca2+ signaling plays an important role, it does not fully explain the scope for regulating ATP production. Emerging evidence suggests that additional signaling systems operating alongside the Ca2+ signaling contribute to the control of mitochondrial ATP production, a topic requiring further investigation.

Optogenetics and chemogenetics have transformed how physiologists interrogate biological systems by enabling precise control over protein activity and cellular function. Optogenetics uses light-sensitive proteins for rapid and localized control, while chemogenetics employs small molecules to trigger or block specific pathways with systemic and sustained effects. These tools have advanced research in areas such as brain function, heart rhythm, immune response, and gene regulation. They have been applied to disease models that include epilepsy, metabolic and cardiovascular diseases, immunoinflammatory disorders, and cancer. Clinical applications are emerging, such as optogenetic therapies for vision restoration and chemogenetic safety switches in engineered immune cells. In this review, we categorize these tools by their mechanisms of action, compare their advantages and limitations, and discuss strategies to improve their precision, efficiency, and translational capability. As these technologies continue to evolve, they offer powerful approaches to dissect complex physiological processes and drive innovative therapeutic interventions.

Whole-body nutrient homeostasis is critical for healthy growth, successful reproduction, and survival. We propose a conceptual framework emphasizing the role of brain nutrient sensing in mediating adaptive responses for the maintenance of nutrient homeostasis. Specialized brain nutrient-sensing cells monitor nutrients and meal-related signals, provide feedback responses to maintain internal nutrient availability, and adapt physiological functions according to environmental nutrient fluctuations. Maladaptive functioning of these pathways may underlie multiple pathophysiological conditions, including cardiometabolic and neurodegenerative diseases. By examining recent advances, this review highlights the importance of brain nutrient sensing in adaptive systemic physiology and behavior, exploring the potential of these neural pathways as therapeutic targets extending beyond obesity management. Ultimately, the goal of this review is to synthesize current evidence into a coherent framework that guides new mechanistic hypotheses, facilitating deeper investigation into how brain nutrient sensing influences health and contributes to disease pathogenesis.

Primary familial brain calcification (PFBC) is a dominantly or recessively inherited neurodegenerative disease characterized by bilateral basal ganglia calcifications. Patients affected by PFBC present with diverse motor and nonmotor symptoms. Mutations in seven genes (SLC20A2, XPR1, PDGFB, PDGFRB, MYORG, NAA60, and JAM2) are associated with PFBC. PFBC genes encode proteins that comprise inorganic phosphate transporters, growth factor and its receptor, a cell adhesion molecule, and enzymes. It remains to be determined whether these proteins interact within a single disrupted pathway or whether mutations affect distinct pathways in the same cell type. Although vessel calcification is a diagnostic criterion of PFBC, its causal role in neurodegeneration needs to be established. This review provides an overview of PFBC genes, including animal models that have yielded insights into the underlying pathophysiologic mechanisms, such as the role of specific cell types in the progression of vascular calcification.

Hypertrophic cardiomyopathy (HCM) is the most common myocardial genetic disease characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction with preserved or elevated ejection fraction. Thirty-five years after the identification of the first genetic variant in myosin heavy chain 7, other variants have been discovered in numerous components of the sarcomere, pointing to a primary defect in cardiomyocyte contractility. Still, a large portion of HCM patients does not have a pathogenic variant and others present with LVH of another genetic origin. Research has uncovered a primary driver of hypercontractility at the sarcomere level and diverse molecular and cellular mechanisms contributing to HCM, including alterations of calcium handling and proteolysis, microtubule modifications, energy deficiency, and the impact of noncardiomyocyte cell types. These discoveries have fueled preclinical and translational research, leading to the development of myosin inhibitors, which are now on the market, and gene-based therapeutic products. This review summarizes current knowledge on the genetics, mechanisms, and targeted treatments of HCM.